CCL5/CCR5 signaling modulates depression-relevant behavior, neuronal oscillations, and long-term depression of synaptic activity.

Abstract

Major depressive disorder (MDD) is a debilitating disorder, often associated with perseverative thinking and anxiety. Localized reductions in pyramidal cell activity may contribute to associated symptoms, and effective antidepressant treatments typically enhance overall neuronal excitation. CCL5 is a chemokine that has been shown to reduce excitatory-neuronal activity, and is also increased with MDD and conditions that increase MDD risk. Here, we investigate the CCL5/CCR5 axis for its ability to modulate depression-relevant endpoints that are diminished in MDD, including neuronal oscillations, as well as biochemical and behavioral correlates of the disorder. In comparison to wildtype mice, CCR5 knockouts had increased gamma and theta power, and stronger theta/high-gamma phase amplitude coupling during dark-cycle EEG recordings. Compared to strain-matched wildtype mice, CCR5 knockouts also demonstrated reduced anxiety, increased sucrose preference, and improved associative memory. Proteomic analysis of the hippocampus showed that CCR5 knockouts had reduced levels of the GABA receptor alpha-4 subunit, which mediates tonic inhibition and restricts pyramidal cell plasticity. In complementary primary neuronal culture studies, CCL5 diminished GSK-3{beta} activity and impaired NMDA-dependent long-term depression (LTD), a form of plasticity that promotes cognitive flexibility. In addition, CCL5 signaling increased parvalbumin expression in GABAergic neurons through a CCR5-dependent manner. In combination with the ability of CCR5 to restrain gamma oscillation power and LTD, our data raise the possibility that CCL5/CCR5 signaling inhibits neuronal excitation through increased PV+ interneuron activity. Moreover, data are consistent with the possibility that CCR5 antagonists might share the ability of established antidepressants to both increase PC excitation and reduce PC inhibition. Significance StatementMajor depressive disorder (MDD) is a global leading cause of disability, and is associated with increased chemokine activation and inflammation. In this study, we investigate how the CCR5/CCL5 chemokine axis regulates behavioral and cognitive endpoints associated with MDD. This study aims to provide insight to how chemokine signaling underlies mood and behavioral symptoms of neuropsychiatric disorders. We hope this research supports further investigation of CCR5 antagonists for MDD and related mood and anxiety disorders.